Sj¿gren’s syndrome (SS) is a chronic autoimmune disease that inflicts damage and dysfunction to salivary and
lacrimal glands and many other organs, resulting in dry mouth, dry eyes and various systemic health problems.
SS affects the oral and systemic health and life quality of 2-4 million Americans, with no cure or effective
biological therapies currently available. An urgent need in SS research is to better understand the causes and
pathogenic processes of this highly complex and multi-factorial disease, and to identify critical new therapeutic
targets for the development of effective and targeted therapies for this high-impact autoimmune disease. The
goal of this project is to define the previously unexplored role of cytokine interleukin-22 (IL-22) in vivo in the
pathogenic development of salivary gland disorder in SS. Our preliminary studies have generated strong
evidence that excessive IL-22, a cytokine with well-documented epithelial tissue-protective function, can cause
salivary gland tissue damage and secretory hypofunction in both normal and SS-prone mice. In this proposed
study, we will test the central hypothesize that in SS disease, endogenously produced IL-22 critically
contributes to the pathological changes and secretory dysfunction of the salivary glands. We will test this
hypothesis in two mouse models of human SS disease. In Aim 1 of the study, we will determine the in vivo
function of endogenous IL-22 in the development of salivary gland pathologies and dysfunction through
antibody-mediated neutralization of IL-22 in the non-obese diabetic mouse, a spontaneous SS disease model.
In Aim 2, we will define the role of endogenous IL-22 in SS by using IL-22 gene-deficient mice and an
autoantigen-induced SS disease model. In both aims, we will examine how the ablation of endogenous IL-22
activity affects the development of SS-like salivary gland disorder by assessing the damage, inflammation,
salivary secretion and molecular changes of salivary gland tissues. Successful completion of this study will for
the first time define the salivary gland- and SS disease-specific role of IL-22. It will also pave the foundation for
further investigation and elucidation of the biology, functional specificity and plasticity, and therapeutic potential
of IL-22 in SS disease and various other epithelial tissue autoimmune inflammatory disorders.